Cell-surface products of the major histocompatibility complex (MHC) are thought to be the principal elements responsible for immune regulation and control of immune-mediated rejection of transplanted foreign tissue. Although much has been learned in recent years regarding the structure of MHC molecules and their role in antigen presentation, we still lack a complete understanding of subtle features of T-cell and peptide interactions with the MHC as well as the functional consequences of T-cell receptor (TcR) recognition of MHC molecules on different types of cells. The following single aim is based on the hypothesis that a relationship exists between the expression of certain T-cell immunoregulatory functions and the context in which a T-cell recognizes antigen in association with particular MHC molecules: We will continue to investigate the function, genetic restriction and antigen specificity of T-lymphocyte clones (TLCs) directed at influenza virus HA determinants but restricted by different interaction products encoded within the HLA-D subregions, HLA-DR, DQ and DP. These features will be examined using several different approaches: 1.Synthetic HA peptides will be used to probe the antigen specificities of TLCs. 2.The binding of radiolabeled peptides to DR, DQ and DP molecules will be investigated. 3.Peptide recognition will be examined using antigen presenting cells (APCs) transfected with normal class II genes and those encoding specifically altered molecules. 4.The specificities of TLCs will be correlated with sequence studies of their TcR genes. 5.The "Ir gene" effects of influenza HA peptides will be studied in binding and functional assays. 6.Monoclonal antibodies (MoAbs) will be used to modulate specific TLC responses to explore the relationships among class II isotype-specific restriction, determinant selection and induction of functional subsets of T-cells. These approaches in addition to more classical ones developed in our laboratory will be used to address the following questions: 1.Do different D--subregion class II molecules restrict responses to different portions of the HA molecule? 2.Is there a correlation between the TcR sequence or T-cell function expressed and the antigenic determinant or MHC molecule recognized? 3.Can anti-class II monoclonal antibodies modulate responses to particular viral determinants at either the specificity or functional levels?